Cotoretigene Toliparvovec Could Improve Visual Function in XLRP

A post-hoc analysis of the XIRIUS and XOLARIS trials suggest the gene therapy improved some visual function for patients with XLRP, but the reported SAEs require further safety assessments.

A post-hoc analysis of two clinical trials investigating the treatment of x-linked retinitis pigmentosa (XLRP) linked cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy to improvements in visual function at 12 months, but indicated the need for further safety evaluations.1

Among 18 participants enrolled in the Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, those who received the 4 highest doses of cotoretigene toliparvovec saw early improvements in retinal sensitivity. By comparison, one of 103 untreated participants in the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study subgroup saw improved retinal sensitivity.

“Considering that serious adverse events [SAEs] of reduced visual acuity [VA] and eye inflammation were observed, additional data from these studies will further assess the safety and visual evaluations of a single subretinal injection of cotoretigene toliparvovec in individuals with RPGR-variant XLRP and natural progression of the disease,” wrote the XOLARIS Study Group.1

Previous six-month results from the phase 1/2 XIRIUS study indicated that 7 of 18 participants experienced gains in visual function in eyes dosed with cotoretigene toliparvovec gene therapy beginning at month 1 and sustained at month 6. The 12-month findings assessed cotoretigene toliparvovec by comparing dosed eyes with untreated fellow eyes in the XIRIUS study and eyes from a subgroup of untreated individuals with similar baseline characteristics in the XOLARIS trial.

Part 1 of the XIRIUS trial was a phase 1, dose-escalation study enrolling 18 male adults between March 2017 and October 2018 with genetically confirmed RPGR-variant XLRP with active disease. Participants were required to have best-corrected visual acuity (BCVA) better than or equal to light perception, 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2 - 3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4 - 6).

A subgroup of male participants from the XOLARIS clinical study 18 years and older who met the inclusion criteria of XIRIUS part 1 were then included as a comparator group. Both eyes were required to have BCVA greater than or equal to 34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline in this group.

The primary safety endpoints were identified as the incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs) over 24 months. Secondary endpoints consisted of changes from baseline in retinal sensitivity and change from baseline in low-luminance VA at 12 months. Data were analyzed in June 2021.

Upon analysis, cotoretigene toliparvovec in the 4 highest dose cohorts was associated with an early and sustained therapeutic benefit. At month 1, half of participants (6 of 12) in cohorts 3 to 6 met the responder definition. Through month 12 of follow-up, the improvements in retinal sensitivity were maintained in 4 of 12 participants (33%).

Among the 6 responders, the mean change from baseline in mean central retinal sensitivity among dosed eyes at month 12 was 5.1 dB, compared with –0.9 dB in untreated fellow eyes. Investigators report only a single untreated participant (1%) in the XOLARIS study subgroup met the responder definition in the study eye.

They additionally observed improvements in LLVA response in cohorts 3 to 6 of the XIRIUS trial in dosed eyes as early as month 1 and sustained through 12 months of follow-up. Among those with available baseline LLVA assessment score, improvements in LLVA response (gain of ≥15 ETDRS letters) at month 12 were observed in 3 dosed eyes (27%) compared with 1 untreated fellow eye.

Safety measures revealed cotoretigene toliparvovec was not associated with any DLTs. Overall data show 73 adverse events occurred in the dosed eyes in the XIRIUS trial, with most events occurring in the top 4 dosing cohorts.

Most treatment-emergent adverse events in the dosed eye were mild (n = 10, 55 of 73 events) and resolved completely (all participants, 60 of 73 events). Two participants experienced serious adverse events of reduced visual acuity and one participant experienced a serious adverse event of noninfective retinitis that was considered associated with the study procedure and study drug.

Based on this analysis, investigators believe the data “support pursuit of additional clinical trials with cotoretigene toliparvovec."


  1. von Krusenstiern L, Liu J, Liao E, et al. Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations. JAMA Ophthalmol. Published online February 09, 2023. doi:10.1001/jamaophthalmol.2022.6254